WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lack of Interchangeability between Botulinum Toxin
Products

The potency Units of BOTOX are specific to the
preparation and assay method utilized. They are not interchangeable with other
preparations of botulinum toxin products and, therefore, units of biological
activity of BOTOX cannot be compared to nor converted into units of any other
botulinum toxin products assessed with any other specific assay method [see DOSAGE
AND ADMINISTRATION, DESCRIPTION].

Spread of Toxin Effect

Postmarketing safety data from BOTOX and other approved
botulinum toxins suggest that botulinum toxin effects may, in some cases, be
observed beyond the site of local injection. The symptoms are consistent with
the mechanism of action of botulinum toxin and may include asthenia,
generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia,
dysarthria, urinary incontinence, and breathing difficulties. These symptoms
have been reported hours to weeks after injection. Swallowing and breathing
difficulties can be life threatening and there have been reports of death
related to spread of toxin effects. The risk of symptoms is probably greatest
in children treated for spasticity but symptoms can also occur in adults
treated for spasticity and other conditions, and particularly in those patients
who have an underlying condition that would predispose them to these symptoms.
In unapproved uses, including spasticity in children, and in approved
indications, symptoms consistent with spread of toxin effect have been reported
at doses comparable to or lower than doses used to treat cervical dystonia.
Patients or caregivers should be advised to seek immediate medical care if
swallowing, speech or respiratory disorders occur.

No definitive serious adverse event reports of distant
spread of toxin effect associated with dermatologic use of BOTOX/BOTOX Cosmetic
at the labeled dose of 20 Units (for glabellar lines) or 100 Units (for severe
primary axillary hyperhidrosis) have been reported.

No definitive serious adverse event reports of distant
spread of toxin effect associated with BOTOX for blepharospasm at the
recommended dose (30 Units and below), strabismus, or for chronic migraine at
the labeled doses have been reported.

Hypersensitivity Reactions

Serious and/or immediate hypersensitivity reactions have
been reported. These reactions include anaphylaxis, serum sickness, urticaria,
soft tissue edema, and dyspnea. If such a reaction occurs, further injection of
BOTOX should be discontinued and appropriate medical therapy immediately
instituted. One fatal case of anaphylaxis has been reported in which lidocaine
was used as the diluent, and consequently the causal agent cannot be reliably
determined.

Dysphagia and Breathing Difficulties in Treatment of
Cervical Dystonia

Treatment with BOTOX and other botulinum toxin products
can result in swallowing or breathing difficulties. Patients with preexisting
swallowing or breathing difficulties may be more susceptible to these
complications. In most cases, this is a consequence of weakening of muscles in
the area of injection that are involved in breathing or swallowing. When
distant effects occur, additional respiratory muscles may be involved.

Deaths as a complication of severe dysphagia have been
reported after treatment with botulinum toxin. Dysphagia may persist for
several months, and require use of a feeding tube to maintain adequate
nutrition and hydration. Aspiration may result from severe dysphagia and is a
particular risk when treating patients in whom swallowing or respiratory
function is already compromised.

Treatment of cervical dystonia with botulinum toxins may
weaken neck muscles that serve as accessory muscles of ventilation. This may result
in a critical loss of breathing capacity in patients with respiratory disorders
who may have become dependent upon these accessory muscles. There have been
postmarketing reports of serious breathing difficulties, including respiratory
failure, in cervical dystonia patients.

Patients with smaller neck muscle mass and patients who
require bilateral injections into the sternocleidomastoid muscle have been
reported to be at greater risk for dysphagia. Limiting the dose injected into
the sternocleidomastoid muscle may reduce the occurrence of dysphagia.
Injections into the levator scapulae may be associated with an increased risk
of upper respiratory infection and dysphagia.

Patients treated with botulinum toxin may require
immediate medical attention should they develop problems with swallowing,
speech or respiratory disorders. These reactions can occur within hours to
weeks after injection with botulinum toxin [see ADVERSE REACTIONS].

Pulmonary Effects of BOTOX in Patients with Compromised
Respiratory Status Treated for Spasticity or for Detrusor Overactivity
associated with a Neurologic Condition

Patients with compromised respiratory status treated with
BOTOX for upper limb spasticity should be monitored closely. In a double-blind,
placebo-controlled, parallel group study in patients with stable reduced
pulmonary function (defined as FEV1 40-80% of predicted value and FEV1/FVC
≤ 0.75), the event rate in change of Forced Vital Capacity ≥ 15% or
≥ 20% was generally greater in patients treated with BOTOX than in
patients treated with placebo (see Table 4).

Table 4: Event rate per patient treatment cycle among
patients with reduced lung function who experienced at least a 15% or 20%
decrease in forced vital capacity from baseline at Week 1, 6, 12 post-injection
with up to two treatment cycles with BOTOX or placebo

BOTOX 360 Units

BOTOX 240 Units

Placebo

≥ 15%

≥ 20%

≥ 15%

≥ 20%

≥ 15%

≥ 20%

Week 1

4%

0%

3%

0%

7%

3%

Week 6

7%

4%

4%

2%

2%

2%

Week 12

10%

5%

2%

1%

4%

1%

Differences from placebo were
not statistically significant

In patients with reduced lung
function, upper respiratory tract infections were also reported more frequently
as adverse reactions in patients treated with BOTOX than in patients treated
with placebo.

In an ongoing double-blind,
placebo-controlled, parallel group study in adult patients with detrusor
overactivity associated with a neurologic condition and restrictive lung
disease of neuromuscular etiology [defined as FVC 50-80% of predicted value in
patients with spinal cord injury between C5 and C8, or MS] the event rate in
change of Forced Vital Capacity ≥ 15% or ≥ 20% was generally greater
in patients treated with BOTOX than in patients treated with placebo (see Table
5).

Table 5: Number and percent
of patients experiencing at least a 15% or 20% decrease in FVC from baseline at
Week 2, 6, 12 post-injection with BOTOX or placebo

BOTOX 200 Units

Placebo

≥ 15%

≥ 20%

≥ 15%

≥ 20%

Week 2

0/12 (0%)

0/12 (0%)

1/11 (9%)

0/11 (0%)

Week 6

2/11 (18%)

1/11 (9%)

0/11 (0%)

0/11 (0%)

Week 12

0/11 (0%)

0/11 (0%)

0/6 (0%)

0/6 (0%)

Corneal Exposure and Ulceration
in Patients Treated with BOTOX for Blepharospasm

Reduced blinking from BOTOX
injection of the orbicularis muscle can lead to corneal exposure, persistent
epithelial defect, and corneal ulceration, especially in patients with VII
nerve disorders. Vigorous treatment of any epithelial defect should be
employed. This may require protective drops, ointment, therapeutic soft contact
lenses, or closure of the eye by patching or other means.

Retrobulbar Hemorrhages in
Patients Treated with BOTOX for Strabismus

During the administration of
BOTOX for the treatment of strabismus, retrobulbar hemorrhages sufficient to
compromise retinal circulation have occurred. It is recommended that
appropriate instruments to decompress the orbit be accessible.

Bronchitis was reported more
frequently as an adverse reaction in patients treated for upper limb spasticity
with BOTOX (3% at 251 Units-360 Units total dose), compared to placebo (1%). In
patients with reduced lung function treated for upper limb spasticity, upper
respiratory tract infections were also reported more frequently as adverse
reactions in patients treated with BOTOX (11% at 360 Units total dose; 8% at
240 Units total dose) compared to placebo (6%).

Autonomic Dysreflexia in
Patients Treated for Detrusor Overactivity associated with a Neurologic
Condition

Autonomic dysreflexia
associated with intradetrusor injections of BOTOX could occur in patients
treated for detrusor overactivity associated with a neurologic condition and
may require prompt medical therapy. In clinical trials, the incidence of
autonomic dysreflexia was greater in patients treated with BOTOX 200 Units
compared with placebo (1.5% versus 0.4%, respectively).

Urinary Tract Infections in
Patients with Overactive Bladder

BOTOX increases the incidence
of urinary tract infection [see ADVERSE REACTIONS]. Clinical trials for
overactive bladder excluded patients with more than 2 UTIs in the past 6 months
and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX
for the treatment of overactive bladder in such patients and in patients with
multiple recurrent UTIs during treatment should only be considered when the
benefit is likely to outweigh the potential risk.

Urinary Retention in Patients
Treated for Bladder Dysfunction

Due to the risk of urinary
retention, treat only patients who are willing and able to initiate
catheterization post-treatment, if required, for urinary retention.

In patients who are not
catheterizing, post-void residual (PVR) urine volume should be assessed within
2 weeks post-treatment and periodically as medically appropriate up to 12
weeks, particularly in patients with multiple sclerosis or diabetes mellitus.
Depending on patient symptoms, institute catheterization if PVR urine volume
exceeds 200 mL and continue until PVR falls below 200 mL. Instruct patients to
contact their physician if they experience difficulty in voiding as
catheterization may be required.

The incidence and duration of
urinary retention is described below for patients with overactive bladder and
detrusor overactivity associated with a neurologic condition who received BOTOX
or placebo injections.

Overactive Bladder

In double-blind, placebo-controlled
trials in patients with OAB, the proportion of subjects who initiated clean
intermittent catheterization (CIC) for urinary retention following treatment
with BOTOX or placebo is shown in Table 6. The duration of post-injection
catheterization for those who developed urinary retention is also shown.

Table 6: Proportion of
Patients Catheterizing for Urinary Retention and Duration of Catheterization
following an injection in double-blind, placebo-controlled clinical trials in
OAB

Timepoint

BOTOX 100 Units
(N=552)

Placebo
(N=542)

Proportion of Patients Catheterizing for Urinary Retention

At any time during complete treatment cycle

6.5% (n=36)

0.4% (n=2)

Duration of Catheterization for Urinary Retention (Days)

Median

63

11

Min, Max

1, 214

3, 18

Patients with diabetes mellitus
treated with BOTOX were more likely to develop urinary retention than those
without diabetes, as shown in Table 7.

Table 7: Proportion of
Patients Experiencing Urinary Retention following an injection in double-blind,
placebo-controlled clinical trials in OAB according to history of Diabetes
Mellitus

Patients with Diabetes

Patients without Diabetes

BOTOX 100 Units
(N=81)

Placebo
(N=69)

BOTOX 100 Units
(N=526)

Placebo
(N=516)

Urinary retention

12.3% (n=10)

0

6.3% (n=33)

0.6% (n=3)

Detrusor Overactivity
associated with a Neurologic Condition

In double-blind,
placebo-controlled trials in patients with detrusor overactivity associated
with a neurologic condition, the proportion of subjects who were not using
clean intermittent catheterization (CIC) prior to injection and who
subsequently required catheterization for urinary retention following treatment
with BOTOX or placebo is shown in Table 8. The duration of post-injection
catheterization for those who developed urinary retention is also shown.

Table 8: Proportion of
Patients not using CIC at baseline and then Catheterizing for Urinary Retention
and Duration of Catheterization following an injection in double-blind,
placebo-controlled clinical trials

Timepoint

BOTOX 200 Units
(N=108)

Placebo
(N=104)

Proportion of Patients Catheterizing for Urinary Retention

At any time during complete treatment cycle

30.6% (n=33)

6.7% (n=7)

Duration of Catheterization for Urinary Retention (Days)

Median

289

358

Min, Max

1, 530

2, 379

Among patients not using CIC at
baseline, those with MS were more likely to require CIC post-injection than
those with SCI (see Table 9).

Table 9: Proportion of
Patients by Etiology (MS and SCI) not using CIC at baseline and then
Catheterizing for Urinary Retention following an injection in double-blind,
placebo-controlled clinical trials

Timepoint

MS

SCI

BOTOX 200 Units
(N=86)

Placebo
(N=88)

BOTOX 200 Units
(N=22)

Placebo
(N=16)

At any time during complete treatment cycle

31% (n=27)

5% (n=4)

27% (n=6)

19% (n=3)

Human Albumin and Transmission
of Viral Diseases

This product contains albumin,
a derivative of human blood. Based on effective donor screening and product
manufacturing processes, it carries an extremely remote risk for transmission
of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob
disease (CJD) is also considered extremely remote. No cases of transmission of
viral diseases or CJD have ever been reported for albumin.

Patient Counseling Information

Provide a copy of the
Medication Guide and review the contents with the patient.

Swallowing, Speaking or
Breathing Difficulties, or Other Unusual Symptoms

Advise patients to inform their
doctor or pharmacist if they develop any unusual symptoms (including difficulty
with swallowing, speaking, or breathing), or if any existing symptom worsens [see
BOXED WARNING and WARNINGS AND PRECAUTIONS].

Ability to Operate Machinery or Vehicles

Advise patients that if loss of strength, muscle
weakness, blurred vision, or drooping eyelids occur, they should avoid driving
a car or engaging in other potentially hazardous activities.

Voiding Symptoms after Bladder Injections

After bladder injections for urinary incontinence, advise
patients to contact their physician if they experience difficulties in voiding
or burning sensation upon voiding.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals have not been performed to
evaluate the carcinogenic potential of BOTOX.

Impairment of Fertility

In fertility studies of BOTOX (4, 8, or 16 Units/kg) in
which either male or female rats were injected intramuscularly prior to mating
and on the day of mating (3 doses, 2 weeks apart for males, 2 doses, 2 weeks
apart for females) to untreated animals, reduced fertility was observed in
males at the intermediate and high doses and in females at the high dose. The
no-effect doses for reproductive toxicity (4 Units/kg in males, 8 Units/kg in
females) are approximately equal to the average high human dose for upper limb
spasticity of 360 Units on a body weight basis (Units/kg).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in
pregnant women. BOTOX should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.

When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly
to pregnant mice or rats two times during the period of organogenesis (on
gestation days 5 and 13), reductions in fetal body weight and decreased fetal
skeletal ossification were observed at the two highest doses. The no-effect
dose for developmental toxicity in these studies (4 Units/kg) is approximately
0.7 times the average high human dose for upper limb spasticity of 360 Units on
a body weight basis (Units/kg).

When BOTOX was administered intramuscularly to pregnant
rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or
0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in
rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal
skeletal ossification were observed at the two highest doses in rats and at the
highest dose in rabbits. These doses were also associated with significant
maternal toxicity, including abortions, early deliveries, and maternal death.
The developmental no-effect doses in these studies of 1 Unit/kg in rats and
0.25 Units/kg in rabbits are less than the average high human dose based on
Units/kg.

When pregnant rats received single intramuscular
injections (1, 4, or 16 Units/kg) at three different periods of development
(prior to implantation, implantation, or organogenesis), no adverse effects on
fetal development were observed. The developmental no-effect level for a single
maternal dose in rats (16 Units/kg) is approximately 3 times the average high
human dose based on Units/kg.

Nursing Mothers

It is not known whether BOTOX is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
BOTOX is administered to a nursing woman.

Pediatric Use

Bladder Dysfunction

Safety and effectiveness in patients below the age of 18
years have not been established.

Prophylaxis of Headaches in Chronic Migraine

Safety and effectiveness in patients below the age of 18
years have not been established.

Spasticity

Safety and effectiveness in patients below the age of 18
years have not been established.

Axillary Hyperhidrosis

Safety and effectiveness in patients below the age of 18
years have not been established.

Cervical Dystonia

Safety and effectiveness in pediatric patients below the
age of 16 years have not been established.

Blepharospasm and Strabismus

Safety and effectiveness in pediatric patients below the
age of 12 years have not been established.

Geriatric Use

Overall, with the exception of Overactive Bladder (see
below), clinical studies of BOTOX did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. There were
too few patients over the age of 75 to enable any comparisons. In general, dose
selection for an elderly patient should be cautious, usually starting at the
low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.

Overactive Bladder

Of 1242 overactive bladder patients in placebo-controlled
clinical studies of BOTOX, 41.4% (n=514) were 65 years of age or older, and
14.7% (n=182) were 75 years of age or older. Adverse reactions of UTI and urinary
retention were more common in patients 65 years of age or older in both placebo
and BOTOX groups compared to younger patients (see Table 15). Otherwise, there
were no overall differences in the safety profile following BOTOX treatment
between patients aged 65 years and older compared to younger patients in these
studies.

Table 15: Incidence of Urinary Tract Infection and
Urinary Retention according to Age Group during First Placebo-controlled
Treatment, Placebo-controlled Clinical Trials in Patients with OAB

Adverse Reactions

< 65 Years

65 to 74 Years

≥ 75 Years

BOTOX 100 Units
N=344

Placebo
N=348

BOTOX 100 Units
N=169

Placebo
N=151

BOTOX 100 Units
N=94

Placebo
N=86

Urinary tract infection

73 (21%)

23 (7%)

51 (30%)

20 (13%)

36 (38%)

16 (19%)

Urinary retention

21 (6%)

2 (0.6%)

14 (8%)

0 (0%)

8 (9%)

1 (1%)

Observed effectiveness was
comparable between these age groups in placebo-controlled clinical studies.

Last reviewed on RxList: 2/4/2013
This monograph has been modified to include the generic and brand name in many instances.